Mechanism of Action
Flucytosine is taken up by fungal organisms via the enzyme cytosine permease. Inside the fungal cell, flucytosine is rapidly converted to fluorouracil by the enzyme cytosine deaminase. Fluorouracil exerts its antifungal activity through the subsequent conversion into several active metabolites, which inhibit protein synthesis by being falsely incorporated into fungal RNA or interfere with the biosynthesis of fungal DNA through the inhibition of the enzyme thymidylate synthetase.
Activity In Vitro
Flucytosine exhibited activity against Candida species and Cryptococcus neoformans. In vitro activity of flucytosine is affected by the test conditions. It is essential to follow the approved standard method guidelines.1
No interpretive criteria have been established for Cryptococcus neoformans. 1
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of yeasts to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 with standardized inoculum concentrations and standardized concentrations of flucytosine powder. The MIC values should be interpreted according to the following criteria:
| MIC(µg/mL)|| Interpretation|
| ≤4|| Susceptible (S)|
| 8-16|| Intermediate (I)|
| ≥32|| Resistant (R)|
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected. Because of other significant host factors, in vitro susceptibility may not correlate with clinical outcomes.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard flucytosine powder should provide the following MIC values:
Acceptable ranges of MICs (µg/mL) for control strains for 48-hour reference broth macrodilution testing:
| Microorganism || MIC(µg/mL) || [% of data included] |
| Candida parapsilosis ||ATCC 22019||0.12-0.5||[98.6%]|
| Candida krusei ||ATCC 6258||4.0-16||[96.8%]|
Acceptable ranges of MICs (µg/mL) for control strains for 24-hour and 48-hour reference broth microdilution testing:
| MIC (µg/mL) ranges for microdilution testing |
|Microorganism||Range||Mode||% of Data|
|Range||Mode||% of Data |
| Candida |
| Candida krusei |
Flucytosine resistance may arise from a mutation of an enzyme necessary for the cellular uptake or metabolism of flucytosine or from an increased synthesis of pyrimidines, which compete with the active metabolites of flucytosine (fluorinated antimetabolites). Resistance to flucytosine has been shown to develop during monotherapy after prolonged exposure to the drug.
Antifungal synergism between flucytosine and polyene antibiotics, particularly amphotericin B has been reported in vitro. Ancobon is usually administered in combination with amphotericin B due to lack of cross-resistance and a reported synergistic activity of both drugs.